The goals of this project involve understanding the molecular genetic defects present in neoplastic conditions of the female genital tract, including endometrial and ovarian carcinoma, uterine sarcoma and uterine leiomyoma (fibroids). Related studies involve molecular genetic analyses of additional cancers that may share some common hormonal aspects such as the breast or prostate. Significant progress has been made in defining the relevant oncogenes and tumor suppressor genes involved in the pathobiology of endometrial carcinoma. In particular, we have defined a major role for the PTEN lipid phosphatase in this cancer type. Many endometrial cancers do not contain mutation of genes such as PTEN, P53, KRAS2 or display the microsatellite instability phenotype(MSI). Microsatellite instability is the result of epigenic silencing of the MLH1 gene in most endometrial cancers with MSI suggesting there development is in part mediated by epigenetic phenomena. Significant effort will be directed towards understanding what epigenetic changes characterize the various types of endometrial cancer. Related to this concept is the identification of genes which display altered mRNA or protein levels which are ultimately a consequence of epigenetic phenomena. Global mRNA and protein expression profiling of uterine neoplasias will be a major focus of this project. in this regard significant progress has been made in gene profiling studies on this most common gynecologic malignancy.